Many antibiotics act by interfering with the biosynthesis of bacterial cell walls (Strominger et al. J. Biol. Chem. 234:3263 (1959)). The completion of bacterial cell wall synthesis is mediated by enzymes termed penicillin-binding proteins (PBPs) which cross-link different peptidoglycan chains. In particular, PBPs link the penultimate D-Ala residue of a peptidoglycan terminating in a N-acyl-D-Ala-D-Ala moiety to the terminal amino group of a lysine residue of another peptidoglycan chain. Glycopeptide transpeptidase is an example of a PBP present in many bacteria.
Most known PBPs are serine peptidases, which have a conserved Ser-X-X-Lys sequence at the active site. The β-lactam family of antibiotics, whose members include penicillins and cephalosporins, inhibit PBPs by forming a covalent bond with the serine hydroxyl group to produce an acyl-enzyme. The enzyme is then unable to carry out the final step in the biosynthesis of the bacterial cell wall. As a result the wall is weakened, becomes permeable to water, and the bacterial cell swells, bursts, and dies.
The simplest kinetic description of the reaction between a bacterial enzyme (Enz) and a β-lactam antibiotic is given in Scheme 1 below: 
In addition to the PBP's, many bacteria also produce a second type of penicillin-recognizing enzyme, known as a β-lactamase. PBPs and β-lactamase exhibit the same kinetics as set forth in Scheme 1 above, but with different rate constants. This difference in rate constants has important consequences. In the case of PBP's, k2>>k3 (i.e., the formation of the acyl-enzyme is much faster than its hydrolysis). The result is that the enzyme is inhibited, and antibacterial activity may be observed. In the case of a β-lactamase, k2≈k3 (i.e., the formation and hydrolysis of the acyl enzyme proceed at comparable rates). These kinetics lead to regeneration of the enzyme, and inactivation of the antibiotic as a result of the net hydrolysis of the β-lactam bond in the deacylation step. The latter sequence of reactions comprises the principle mechanism of bacterial resistance to β-lactam antibiotics. Useful antibacterial activity is generally considered to require k2/k1≧1000M−1 sec−1 and k3≦1×10−4 sec−1.
Resistance to antibiotics is a problem of much current concern. Alternatives to existing antibiotics are invaluable when bacteria develop immunity to these drugs or when patients are allergic (approximately 5% of the population is allergic to penicillin). Because of the relatively low cost and relative safety of the β-lactam family of antibiotics, and because many details of their mechanism of action and the mechanism of bacterial resistance are understood, one approach to the problem of resistance is to design new classes of compounds that will complex to and react with a penicillin recognizing enzyme, and be stable to the hydrolysis step. In order to be effective, the antibacterial agent should have the ability to react irreversibly with the active site serine residue of the enzyme.
The crystal structures of β-lactamases from B. licheniformis, S. aureus and E. coli (RTEM) suggest a chemical basis for resistance to β-lactam antibiotics. Apart from the conserved Ser-X-X-Lys active site sequence, these β-lactamases have a conserved Glu166 which participates in the hydrolysis of the acyl-enzyme. It appears that the acylated hydroxyl group of the active site serine and the carboxyl group of Glu 166, together with a water molecule, are involved in the hydrolysis step. The water molecule and the carboxyl group act in concert and this interaction is the source of bacterial resistance to β-lactam antibiotics. Drug design must therefore include a process for the removal or inactivation of this water molecule.
Numerous β-lactam compounds have been developed in the past which are structural analogues of penicillin and can complex to and react with penicillin recognizing enzymes. Like penicillin, such antibiotics are presumed to be conformationally constrained analogues of an N-acyl-D-Ala-D-Ala peptidoglycan moiety, the O═C—N β-lactam bond serving as a bioisostere of the D-Ala-D-Ala peptide bond. Effective antibacterial activity also requires a properly positioned carboxyl group or equivalent and a hydrogen bonding hydroxyl or acylamino group. A computer implemented molecular modeling technique for identifying compounds which are likely to bind to the PBP active site and, thus, are likely to exhibit antibacterial activity has been developed (U.S. Pat. No. 5,552,543).
Some oxazinones having possible biological activity are known in the prior art Khomutov et al. synthesized tetrahydro-1,2-oxazin-3-one (Chem. Abs. 13754a, 1962) and 4-benzamidotetrahydro-1,2-oxazin-3-one (Chem. Abs. 58, 13944b, 1963). The latter compound is also known as N-benzoyl-cyclocanaline. According to Khomutov, cyclocanaline is known to inhibit glutamate-aspartate transaminase and exhibits activity against tuberculosis bacilli. The structure of cyclocanaline is shown in formula (A) below. 
Frankel et al. reported the synthesis of DL-cyclocanaline (4-amino-tetrahydro-1,2-oxazin-3-one) hydrochloride from canaline dihydrochloride in 1969 (J. Chem. Soc. (C) 174601749, 1969) and recognized that DL-cyclocanaline is a higher homologue of the antibiotic cycloserine.